1. Field of Invention
The present invention relates to a process for the preparation of certain known pyrido[1,4]benzodiazepines and novel chemical intermediates therefor.
An important aspect of the process is the utilization of a strong non-nucleophilic base such as sodium hydride to bring about condensation of an aminochloropyridine and an aryl(aminophenyl)methanone in admixture with mobile inert liquid carrier to produce the pyrido[1,4]benzodiazepines. Alternatively, the condensation may be started with titanium tetrachloride and finished with the non-nucleophilic base, in which case novel intermediates are produced and used.
2. Information Disclosure Statement
The aryl substituted pyrido[1,4]benzodiazepines prepared by the process of this invention are disclosed in S. African Pat. No. 81/7866 hereby incorporated by reference and are the subject of a corresponding commonly assigned U.S. continuation application Ser. No. 395,218 filed July 6, 1982, now U.S. Pat. No. 4,447,361, hereby incorporated by reference. In the method of preparation disclosed in these references, amino-halo pyridines and aminoarylphenones are heated neat to give pyrido[1,4]benzodiazepines.
Commonly assigned U.S. application Ser. No. 431,997 filed Sept. 30, 1982, now U.S. Pat. No. 4,480,100, describes preparation of [2-[(nitropyridinyl)amino]phenyl]arylmethanones, useful in preparation of the pyrido[1,4]benzodiazepines, by heating neat a halonitropyridine with an aminoarylphenone.
Heating and reaction of such mixtures as described in the foregoing disclosures involves difficult handling of viscous, sticky reactants and reaction products which adhere to the reaction vessel. In contrast, in the present invention the diazepine ring is formed by a strong non-nucleophilic base such as sodium hydride in a solvent or liquid carrier which provides high mobility, ease of operation and increased yields and direct formation of the sodium salts of the pyrido 1,4-benzoidazepines.
Relating to the preparation of certain chemical intermediates used in the process of the present invention, Yamamoto, M. and Yamamoto H. in Chem. Pharm. Bull. 29(8), 2135-2156 (1981) describe the reaction of 2-amino-4-chlorobenzophenone and an amine in the presence of titanium tetrachloride as represented by the following equation: ##STR2## wherein R.sup.1 =alkyl, cycloalkyl, phenylalkyl, dialkylaminoalkyl and 4-morpholinoalkyl.
Also relating to preparation of certain other intermediates used in the process is a disclosure of phase-transfer catalyzed N-monoalkylation of 2-aminobenzophenones of Mouzin, G., et al, in Synthesis Communications Georg. Thieme Verlag 1981, p. 448-449. as represented by the following equation: ##STR3## wherein R=CH.sub.3, --C.sub.2 H.sub.5 or allyl; X.sup.1 =Cl or Br; X.sup.2 =H, Cl or F.